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Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists

Abstract

Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-α and REV-ERB-β have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.

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Figure 1: SR9011 and SR9009 are synthetic REV-ERB agonists with activity in vivo.
Figure 2: Synthetic REV-ERB ligands alter circadian behaviour and the pattern of expression of core clock genes.
Figure 3: Activation of REV-ERB by SR9011 in vivo results in an increase in energy expenditure and weight loss.
Figure 4: REV-ERB ligands alter the pattern of circadian expression of metabolic genes in the liver, skeletal muscle and adipose tissue.
Figure 5: SR9009 treatment results in a decrease in fat mass and in plasma lipids in diet-induced obese mice.

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Acknowledgements

This work was supported by National Institutes of Health Grants (DK080201, MH092769 and DK089984) and the Howard Hughes Medical Institute. L.A.S. is the recipient of an individual National Research Service Award (DK088499).

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Authors and Affiliations

Authors

Contributions

T.P.B. conceived the project. R.N., Y.S. and T.M.K. synthesized and analysed the ligands. L.A.S., Y.W., S.B., D.J.K. and T.P.B. designed/analysed and/or performed the transfection and biochemical assays. D.J.K. and T.H. designed and performed the CD analysis. T.P.B., L.A.S. and A.A.B. designed, analysed and performed the metabolic studies. Y.W., T.P.B., S.B. and T.L designed/analysed and/or performed the circadian gene expression and behaviour analysis. J.L. performed gene expression analysis. S.-H.Y. and J.S.T. designed and performed the studies using the Per2-luc mouse tissues. M.D.C. performed the pharmacokinetic analysis. T.P.B. wrote the manuscript with input from all of the authors.

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Correspondence to Thomas P. Burris.

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The authors declare no competing financial interests.

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Solt, L., Wang, Y., Banerjee, S. et al. Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature 485, 62–68 (2012). https://doi.org/10.1038/nature11030

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